SILENCING OF THE MAMMARY-DERIVED GROWTH INHIBITOR (MDGI) GENE IN BREAST NEOPLASMS IS ASSOCIATED WITH EPIGENETIC CHANGES

Recently, we reported that breast cancer cell lines fail to express th e gene encoding the fatty acid binding protein mammary derived growth inhibitor (MDGI) and that transfection with an MDGI expression vector results in suppression of the malignant phenotype, suggesting that MDG I is a tumor suppressor gene. We also demonstrated that homozygous del etion and point mutation are not common mechanisms for silencing of th e MDGI gene in human breast neoplasms. We now report that hypermethyla tion of HpaII and HhaI sites upstream of the first exon of the MDGI ge ne, and a SacII site in the first intron, occurs frequently in human b reast cancer cell lines, This distinct methylation pattern is associat ed with loss of transcription and is reversible by treatment with 5-az a-deoxycytidine. Primary breast tumors also exhibited methylation of t he SacII site (19 of 35, 54.3%) and the HpaII and HhaI sites (21 of 35 , 66%), Hypermethylation of these sites was correlated with the absenc e of MDGI mRNA in these tumors. Our results suggest that epimutation o f the MDGI gene leads to silencing, which, in turn, may initiate or co ntribute to progression of breast cancer.